Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.
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DOI：
10.1016/j.cmet.2015.11.011
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发表时间：
2016-02-09
期刊：
影响因子：
29
通讯作者：
Campisi J
中科院分区：
文献类型：
--
作者：
Wiley CD;Velarde MC;Lecot P;Liu S;Sarnoski EA;Freund A;Shirakawa K;Lim HW;Davis SS;Ramanathan A;Gerencser AA;Verdin E;Campisi J
细胞衰老永久阻止细胞增殖，通常伴有多方面的衰老相关分泌表型（SASP）。线粒体功能的丧失会导致许多有丝分裂后组织的功能与年龄相关的下降，但人们对线粒体功能障碍如何影响有丝分裂组织知之甚少。我们在此表明，在增殖的人类细胞中，几种损害线粒体功能的操作会通过缺乏 IL-1 依赖性炎症臂的改良 SASP 诱导衰老生长停滞。经历线粒体功能障碍相关衰老 (MiDAS) 的细胞具有较低的 NAD+/NADH 比率，这会导致生长停滞并通过 AMPK 介导的 p53 激活阻止 IL-1 相关的 SASP。快速产生 mtDNA 突变的早衰小鼠体内 MiDAS SASP 会积累衰老细胞，从而抑制细胞培养中的脂肪生成并刺激角质形成细胞分化。我们的数据确定了一种独特的衰老反应，并提供了线粒体功能障碍驱动衰老表型的机制。
Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.